SMARCA4 ATPase mutations disrupt direct eviction of PRC1 from chromatin
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA349260 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3111660.fastq.gz | Fastqsanger.gz | |||
| SRR3111670.fastq.gz | Fastqsanger.gz | |||
| SRR3111680.fastq.gz | Fastqsanger.gz | |||
| SRR3111690.fastq.gz | Fastqsanger.gz | |||
| SRR3111700.fastq.gz | Fastqsanger.gz |
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Project description:Trithorax-group proteins and their mammalian homologs, including those in BAF (mSWI/SNF) complexes, are known to oppose the activity of Polycomb repressive complexes (PRCs). This opposition underlies the tumor-suppressive role of BAF subunits and is expected to contribute to neurodevelopmental disorders. However, the mechanisms underlying opposition to Polycomb silencing are poorly understood. Here we report that recurrent disease-associated mutations in BAF subunits induce genome-wide increases in PRC deposition and activity. We show that point mutations in SMARCA4 (also known as BRG1) mapping to the ATPase domain cause loss of direct binding between BAF and PRC1 that occurs independently of chromatin. Release of this direct interaction is ATP dependent, consistent with a transient eviction mechanism. Using a new chemical-induced proximity assay, we find that BAF directly evicts Polycomb factors within minutes of its occupancy, thereby establishing a new mechanism for the widespread BAF-PRC opposition underlying development and disease.
| S-EPMC5373480 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2016-10-21 | GSE88968 | GEO
Project description:The packaging of DNA into chromatin plays an important role in transcriptional regulation and nuclear processes. Brahma related gene-1 SMARCA4 (also known as BRG1), the essential ATPase subunit of the mammalian SWI/SNF chromatin remodeling complex, uses the energy from ATP hydrolysis to disrupt nucleosomes at target regions. Although the transcriptional role of SMARCA4 at gene promoters is well-studied, less is known about its role in higher-order genome organization. SMARCA4 knockdown in human mammary epithelial MCF-10A cells resulted in 176 up-regulated genes, including many related to lipid and calcium metabolism, and 1292 down-regulated genes, some of which encode extracellular matrix (ECM) components that can exert mechanical forces and affect nuclear structure. ChIP-seq analysis of SMARCA4 localization and SMARCA4-bound super-enhancers demonstrated extensive binding at intergenic regions. Furthermore, Hi-C analysis showed extensive SMARCA4-mediated alterations in higher-order genome organization at multiple resolutions. First, SMARCA4 knockdown resulted in clustering of intra- and inter- sub-telomeric regions, demonstrating a novel role for SMARCA4 in telomere organization. SMARCA4 binding was enriched at TAD (Topologically Associating Domain) boundaries, and SMARCA4 knockdown resulted in weakening of TAD boundary strength. Taken together, these findings provide a dynamic view of SMARCA4-dependent changes in higher-order chromatin organization and gene expression, identifying SMARCA4 as a novel component of chromatin organization. Hi-C and RNA-seq experiments were conducted in MCF-10A shSCRAM and shSMARCA4 cells. SMARCA4 ChIP-seq was conducted in wildtype MCF-10A cells.
2016-06-02 | E-GEOD-74716 | biostudies-arrayexpress
Project description:We generated a library of Brg variants with mutations in conserved regions of the N-terminal ATPase domain based on mutants observed in primary tumors and cancer cell lines. Heterozygous expression of ATPase mutants leads to increased occupancy of Polycomb Repressive Complex 1 (PRC1) at bivalent CpG-island promoters. Increased PRC1 binding was accompanied by increases in H3K27me3, the mark left by the Polycomb Repressive Complex 2 (PRC2) ~2 kbp away.
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Project description:SMARCA2 and SMARCA4 are two mutually exclusive ATPase subunits of SWI/SNF complex. SMARCA4 deficient lung cancer population selectively depend on SMARCA2 for cancer growth phenotype. Rescue experiments with ectopic expression of wild-type, bromodomain mutant and ATPase dead SMARCA2 and SMARCA4 highlight that ATPase domain is the drug target. In this study, we performed genome-wide microarray and differential gene expression profiling on isogenic lung cancer lines expressing cDNA rescue constructs for wild-type, bromodomain mutant and ATPase dead SMARCA2 and SMARCA4
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Project description:We generated a library of Smarca4 variants with mutations in conserved regions of the N-terminal ATPase domain based on mutants observed in primary tumors and cancer cell lines. Heterozygous expression of Smarca4 ATPase mutants led to decreased accessibility at active enhancers in mouse embryonic stem cells.
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Project description:The packaging of DNA into chromatin plays an important role in transcriptional regulation and nuclear processes. Brahma related gene-1 SMARCA4 (also known as BRG1), the essential ATPase subunit of the mammalian SWI/SNF chromatin remodeling complex, uses the energy from ATP hydrolysis to disrupt nucleosomes at target regions. Although the transcriptional role of SMARCA4 at gene promoters is well-studied, less is known about its role in higher-order genome organization. SMARCA4 knockdown in human mammary epithelial MCF-10A cells resulted in 176 up-regulated genes, including many related to lipid and calcium metabolism, and 1292 down-regulated genes, some of which encode extracellular matrix (ECM) components that can exert mechanical forces and affect nuclear structure. ChIP-seq analysis of SMARCA4 localization and SMARCA4-bound super-enhancers demonstrated extensive binding at intergenic regions. Furthermore, Hi-C analysis showed extensive SMARCA4-mediated alterations in higher-order genome organization at multiple resolutions. First, SMARCA4 knockdown resulted in clustering of intra- and inter- sub-telomeric regions, demonstrating a novel role for SMARCA4 in telomere organization. SMARCA4 binding was enriched at TAD (Topologically Associating Domain) boundaries, and SMARCA4 knockdown resulted in weakening of TAD boundary strength. Taken together, these findings provide a dynamic view of SMARCA4-dependent changes in higher-order chromatin organization and gene expression, identifying SMARCA4 as a novel component of chromatin organization.
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Project description:We investigated transcriptomic effects of a Smarca4 ATPase mutant observed in primary tumors and cancer cell lines. Heterozygous expression of G784E Smarca4 mutant led to transcriptional changes compared to cells expressing only wild-type Smarca4.
2017-10-22 | GSE98469 | GEO
Project description:Mutations in SMARCA4, a central ATPase of the human BAF/PBAF chromatin remodeling complexes, cause developmental abnormalities and promote cancer development. The pathogenic effects of SMARCA4 loss are often linked to the de-regulation of a relatively small number of key target genes. Here, to understand how chromatin remodeling by SMARCA4 results in specific transcriptional perturbations, we used genome engineering to correct a homozygous mutation in SMARCA4 in the well-characterized lung adenocarcinoma A549 cell line and profiled changes in SMARCA2/4 occupancy, chromatin accessibility, histone marks and transcription. Restoration of SMARCA4 causes a dramatic increase in chromatin accessibility at low affinity TF binding sites. Despite the widespread increase in chromatin accessibility, we observe comparatively attenuated changes in gene expression. Although there is a marked correlation between the number of local activated DHSs and the transcriptional responsivity of a gene, the influence of distal DHSs appears modified by a gene's promoter architecture and domain-scale chromatin organization. The largest changes in expression occur for genes in isolated, SMARCA4 sensitive chromatin domains that undergo region-wide chromatin remodeling upon reintroduction of SMARCA4. Our results reveal that interactions between distal enhancers, genome organization, and promoter architecture add transcriptional specificity to the global chromatin effects of BAF/PBAF complex perturbation and target the response to key developmental pathways.
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Project description:Mutations in SMARCA4, a central ATPase of the human BAF/PBAF chromatin remodeling complexes, cause developmental abnormalities and promote cancer development. The pathogenic effects of SMARCA4 loss are often linked to the de-regulation of a relatively small number of key target genes. Here, to understand how chromatin remodeling by SMARCA4 results in specific transcriptional perturbations, we used genome engineering to correct a homozygous mutation in SMARCA4 in the well-characterized lung adenocarcinoma A549 cell line and profiled changes in SMARCA2/4 occupancy, chromatin accessibility, histone marks and transcription. Restoration of SMARCA4 causes a dramatic increase in chromatin accessibility at low affinity TF binding sites. Despite the widespread increase in chromatin accessibility, we observe comparatively attenuated changes in gene expression. Although there is a marked correlation between the number of local activated DHSs and the transcriptional responsivity of a gene, the influence of distal DHSs appears modified by a gene's promoter architecture and domain-scale chromatin organization. The largest changes in expression occur for genes in isolated, SMARCA4 sensitive chromatin domains that undergo region-wide chromatin remodeling upon reintroduction of SMARCA4. Our results reveal that interactions between distal enhancers, genome organization, and promoter architecture add transcriptional specificity to the global chromatin effects of BAF/PBAF complex perturbation and target the response to key developmental pathways.
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